Epigenetic regulators such as the polycomb proteins control critical biological functions in both normal stem cells and aggressive human cancer cell types. A gene signature that includes polycomb genes and additional genes co-regulated with polycomb genes was recently identified. The expression of this signature identifies tumors with the cancer stem cell phenotypes of aggressive growth, metastasis and therapy resistance. Most members of this 11- gene signature encode proteins with well-defined roles in human cancer. However the function of the signature member USP22 remained unknown. We recently reported that USP22 is a previously uncharacterized subunit of the human SAGA transcriptional cofactor complex. Within hSAGA, USP22 deubiquitylates histone H2A and H2B, thereby playing a central role in transcription. Furthermore, USP22 is recruited to specific genes by activators such as the MYC oncoprotein, where it is required for transcription. In support of a functional role within the polycomb/cancer stem cell signature, I have recently shown by genetic depletion that USP22 is required for protecting human cancer cells from death induced by genotoxic stress. In this proposal, I will define the precise biochemical events that USP22 overexpression triggers in aggressive human cancer cells in order to protect them from gentoxic stress and death. Ultimately, I will extend my findings from genetic depletion studies to assess whether pharmacological inhibition of USP22 can also be exploited to selectively induce apoptosis in transformed human cells.